Tumor microenvironment-activated and near-infrared light-driven free radicals amplifier for tetra-modal cancer imaging and synergistic treatment

The tumor microenvironment (TME) exhibits a specific feature of hypoxia, which poses significant challenges for oxygen (O2)-dependent treatments. In this study, we developed an intelligent nanoplatform (PEGylated AIPH@MSN/CDs-MnO2, denoted as A@M/C-Mn) by integrating a photosensitizer of red carbon dots (CDs) with a thermolabile initiator-loaded mesoporous silica nanoparticle (AIPH@MSN, denoted as A@M), and then growing manganese dioxide nanosheets (MnO2 NS) in situ and PEGylating the structure to achieve TMEresponsive synergistic diagnosis and phototherapy against hypoxic tumors. The outer-layer MnO2 NS has the capability to decompose endogenous hydrogen peroxide (H2O2) in the acidic TME, thereby producing O2 to alleviate hypoxia while releasing Mn2+. This process restores the fluorescence (FL) and photodynamic therapy (PDT) properties of the CDs, enhancing singlet oxygen (1O2) generation upon near-infrared (NIR) laser irradiation. Concomitantly, the exposed CDs induce hyperthermia for photothermal therapy (PTT) and promote the decomposition of AIPH to form cytotoxic alkyl radicals (center dot R) for O2-independent PDT. Importantly, the entire treatment process can be monitored through ultrasound (US)/magnetic resonance (MR)/photoacoustic (PA)/FL imaging, owing to O2 production, Mn2+ release, and CDs activation, respectively. Both in vitro and in vivo results provide evidence that A@M/C-Mn represents a promising theranostic nanoagent for hypoxic tumors.